This proposal outlines 1) a study of the molecular biology of the induction process - namely the quasi stringent response in which stable RNA and bulk protein synthesis are transiently inhibited soon after Neurospora is induced to synthesize the enzymes of leucine biosynthesis. This phenomenon, which depends upon the presence of alpha isopropylmalate and the leu-3 ion regulatory product, the leucine regulatory signals, suggest that the physiological consequences of the regulatory response are much greater than imagined heretofore. 2) A study of the regulation of histidine biosynthesis especially as it relates to the regulation of the leucine pathway. It has been found that mutants constitutive for the leucine pathway are resistant to inhibition by aminotriazole, an inhibitor of histidine biosynthesis. Preliminary investigations have led us to believe that some form of facilitative depression is involved but the analysis is complicated by an apparent lack of coordination of histidine enzyme synthesis in response to histidine and leucine pathway specific signals. Our attention is now focused on the coregulation of the two pathways in his leu double mutants. 3) In addition to leucine the regulation of the histidine system has been linked to that of tryptophan, arginine and lysine by what has come to be known as "cross pathway regulation." Although nothing is known about mechanism, our preliminary mutant hunts, which we intend to expand, suggest that the physio-logical extent of the "cross pathway" regulatory circuit can be probed by an analysis of the kinds of aminotriazole resistant mutants obtained after challenge -especially auxotrophic, bradytrophic and regulatory mutants involving reactions participating in the interacting regulatory network. 4) A study of the regulation of the linked nuclear genes that specify the structure of the cytoplasmic and mitochondrial leucyl-tRNA synthetases. These enzymes appear to be regulated reciprocally under normal circumstances. We recently found that the mitochondrial enzyme is overproduced by strains containing cni-3 mutant mitochondria. While cytoplasmic enzyme production by these strains is reduced, the reduction is by no means reciprocally proportional. Experiments are described to study the regulatory interaction and test whether the mitochondrion controls the production of enzymes involved in the processing of material which is eventually incorporated into its structure.